Synthesis and Activity of Benzenesulfonyl Piperazines

doi:10.6023/cjoc202409007

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (7): 2406-2415.DOI: 10.6023/cjoc202409007 Previous Articles Next Articles

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苯磺酰哌嗪类化合物的合成及活性研究

刘江钰^a^,^†, 刘洪涛^b^,^c^,^†, 巫晔翔^d, 张国盛^a, 王玉杰^a, 张煜皓^d, 雷丽娟^d, 许艳妮^d^,^*(), 李文燕^a^,^*()

^a 河北师范大学化学与材料科学学院河北省有机功能分子重点实验室石家庄 050024
^b 河北医科大学第一医院药剂科石家庄 050000
^c 河北省人民医院临床医学研究中心石家庄 050017
^d 中国医学科学院医药生物技术研究所国家新药(微生物)筛选实验室北京 100050

收稿日期:2024-11-08 修回日期:2025-02-28 发布日期:2025-03-07
作者简介:
^† 共同第一作者
基金资助:
河北省自然科学基金(H2022307031); 河北省自然科学基金(H2024205002); 河北省科技厅省级重点实验室绩效补助经费(22567622H)

Synthesis and Activity of Benzenesulfonyl Piperazines

Jiangyu Liu^a, Hongtao Liu^b^,^c, Yexiang Wu^d, Guosheng Zhang^a, Yujie Wang^a, Yuhao Zhang^d, Lijuan Lei^d, Yanni Xu^d^,^*(), Wenyan Li^a^,^*()

^a Hebei Key Laboratory of Organic Functional Molecules, College of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang 050024
^b Department of Pharmacy, the First Hospital of Hebei Medical University, Shijiazhuang 050000
^c Clinical Medical Research Center, Hebei General Hospital, Shijiazhuang 050017
^d National Laboratory for Screening of New Drugs (Microbial), Institute of Medical Biotechnology, Chinese Academy of Medical Sciences, Beijing 100050

Received:2024-11-08 Revised:2025-02-28 Published:2025-03-07
Contact: *E-mail: xuyanniwendeng@hotmail.com; wyli8512@mail.hebtu.edu.cn
About author:
^† These authors contributed equally to this work
Supported by:
Natural Science Foundation of Hebei Province(H2022307031); Natural Science Foundation of Hebei Province(H2024205002); Project of Science and Technology Department of Hebei Province(22567622H)

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Abstract

Adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1) is a critical transporter that mediates cellular cholesterol and other lipophilic substances efflux from macrophages in reverse cholesterol transport (RCT). ABCA1 is the initiation and rate-limiting step of RCT. Therefore, increasing the expression level of ABCA1 is beneficial to inhibit and delay atherosclerosis (AS). ABCA1 expression up-regulator is expected to be a new method for the treatment of AS. A class of compounds containing benzenesulfonyl piperazine skeleton were synthesized and their up-regulated expression activities of ABCA1 were evaluated based on ABCA1-promoter-luc-HepG2 stable transfection cell model. Among them, 5-(4-(2,6- dichlorophenylsulfonyl)-1-piperazinomethyl)-2-furancarboxylic acid (4b) and 2-(4-(2,6-dichlorophenylsulfonyl)-1-piperazi- nyl)thiazole-5-carboxylic acid (4c) had the highest up-regulated expression rates of 308% and 223%, and the EC₅₀ values were 0.03 and 0.008 μmol/L, respectively. They were good up-regulated expression agents of ABCA1. The structure-activity relationship of these compounds was also briefly summarized.

Key words: atherosclerosis, adenosine triphosphate (ATP) binding cassette transporter A1 (ABCA1), ABCA1 up-regulated expression agent, benzenesulfonyl piperazine

Cite this article

Jiangyu Liu, Hongtao Liu, Yexiang Wu, Guosheng Zhang, Yujie Wang, Yuhao Zhang, Lijuan Lei, Yanni Xu, Wenyan Li. Synthesis and Activity of Benzenesulfonyl Piperazines[J]. Chinese Journal of Organic Chemistry, 2025, 45(7): 2406-2415.

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Fig. & Tab. 7

Figure 1. Structures of benzenesulfonyl piperazines

Scheme 1. Synthesis of compounds 3a~3j and 4a~4f Reaction conditions: (i) pyridine, THF; (ii) TFA, DCM; (iii) TEA, DCM; (iv) Cs2CO3, DMF, 120 ℃; (v) THF, 10% NaOH, EtOH, 60 ℃.

Scheme 2. Synthesis of compounds 7a~7f, 8a~8e Reaction conditions: (i) Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 ℃; (ii) THF, conc. H2SO4, NBS, －25 ℃/NCS, 40 ℃; (ⅲ) DCM, TFA, r.t.; (ⅳ) 2,6-dichlorobenzene sulfonyl chloride or 2,6-difluorobenzene sulfonyl chloride, THF, pyridine; (ⅴ) THF, aq. NaOH (ω=10%), EtOH, 60 ℃.

Compd.	Highest up-regulated expression rate/%	EC₅₀/(μmol•L^－1)
3a	105±8	—
3b	142±5	—
3c	129±3	—
3d	210±2	0.40±0.14
3e	198±1	0.15±0.09
3f	179±6	0.58±0.21
3g	137±4	—
3h	145±3	—
3i	150±1	—
3j	117±2	—
4a	182±1	4.19±0.17
4b	308±1	0.03±0.01
4c	223±1	0.008±0.001
4d	201±6	0.17±0.06
4e	227±5	0.11±0.04
4f	140±4	—
7a	169±3	10.18±0.18
7b	179±2	17.54±0.39
7c	172±8	6.98±0.11
7d	212±2	11.47±0.32
7e	203±4	4.89±0.71
7f	145±7	—
8a	146±2	—
8b	129±3	—
8c	164±2	32.25±1.86
8d	215±1	0.14±0.03
8e	210±5	3.73±0.19
6i	200±6	0.41±0.05

Table 1. ABCA1 upregulatory activity of target compounds

Figure 2. Effects of compounds 4b and 4c on ABCA1 mRNA expression in RAW264.7 cells

Figure 3. Effects of compounds 4b and 4c on cholesterol efflux in RAW264.7 cells

Figure 4. Oil red O staining experiment of compounds 4b and 4c

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苯磺酰哌嗪类化合物的合成及活性研究

Synthesis and Activity of Benzenesulfonyl Piperazines

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